Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease

Abstract

BACKGROUND AND PURPOSE Inhibitors of phosphodiesterase 5 (PDE5) affect signalling pathways by elevating cGMP, which is a second messenger involved in processes of neuroplasticity. In the present study, the effects of the PDE5 inhibitor, sildenafil, on the pathological features of Alzheimer's disease and on memory‐related behaviour were investigated. EXPERIMENTAL APPROACH Sildenafil was administered to the Tg2576 transgenic mouse model of Alzheimer's disease and to age‐matched negative littermates (controls). Memory function was analysed using the Morris water maze test and fear conditioning tasks. Biochemical analyses were performed in brain lysates from animals treated with saline or with sildenafil. KEY RESULTS Treatment of aged Tg2576 animals with sildenafil completely reversed their cognitive impairment. Such changes were accompanied in the hippocampus by a reduction of tau hyperphosphorylation and a decrease in the activity of glycogen synthase kinase 3β (GSK3β) and of cyclin‐dependent kinase 5 (CDK5) (p25/p35 ratio). Moreover, sildenafil also increased levels of brain‐derived neurotrophic factor (BDNF) and the activity‐regulated cytoskeletal‐associated protein (Arc) in the hippocampus without any detectable modification of brain amyloid burden. CONCLUSIONS AND IMPLICATIONS Sildenafil improved cognitive functions in Tg2576 mice and the effect was not related to changes in the amyloid burden. These data further strengthen the potential of sildenafil as a therapeutic agent for Alzheimer's disease.

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

“…Finally, the inhibition of HDAC6 may facilitate the degradation of misfolded proteins, such as Aβ and pTau (Sung et al, 2012;Yu et al, 2013;Zhang et al, 2014). Although different studies have demonstrated that HDACi or PDE5i improved cognitive deficits in animal models of AD, their role on amyloid pathology is controversial (Benito et al, 2015;Cuadrado-Tejedor et al, 2011b;Garcia-Barroso et al, 2013;Puzzo et al, 2009;Qing et al, 2008;Ricobaraza et al, 2009;Rumbaugh et al, 2015;Zhang and Schluesener, 2013). These differences may be because of the selectivity and potency of each compound and the different animal models and treatments employed.…”

“…By inhibiting PDE5, CM-414 can restore memory through the activation of the cGMP/CREB pathway that plays an important role in synaptic plasticity (Lu and Hawkins, 2002;Lu et al, 1999). Furthermore, the inhibition of PDE5 might diminish tau phosphorylation by favoring the inactive form of GSK3β (GSK3β-Ser9) (Cuadrado-Tejedor et al, 2011b;GarciaBarroso et al, 2013). On the other hand, through the inhibition of HDAC class I in conjunction with CREB activation, CM-414 may also facilitate the transcription of more specific memory-related genes, thereby reducing the indiscriminate transcription provoked by other HDAC class I inhibitors.…”

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

“…Puzzo et al [130] first demonstrated the preclinical efficacy of PDE5 inhibitors in AD mouse models and the findings were later confirmed by other groups [131][132][133]. Among reported PDE5 inhibitors, tadalafil and sildenafil can penetrate into the brain and ameliorate synaptic, learning, and memory deficits by modulating the cyclic guanosine monophosphate intracellular signaling pathway [130,134].…”

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

“…97 In AD mouse models, cGMP-dependent inactivation of GSK3β by PDE5 inhibitors leads to a decrease in hyperphosphorylated tau in the brain areas involved in learning and memory. 30,32 As tau phosphorylation better correlates with cognitive impairment in AD than amyloid burden, 133 increased hippocampal pAkt and pGSK3β-Ser9 levels have been proposed to underlie the improvements in learning and memory consolidation observed in sildenafil-and tadalafil-treated AD mice. 30,32 Similar activation of the Akt pathway by tadalafil has been proposed to increase cell survival in different peripheral tissues.…”

“…30,32 As tau phosphorylation better correlates with cognitive impairment in AD than amyloid burden, 133 increased hippocampal pAkt and pGSK3β-Ser9 levels have been proposed to underlie the improvements in learning and memory consolidation observed in sildenafil-and tadalafil-treated AD mice. 30,32 Similar activation of the Akt pathway by tadalafil has been proposed to increase cell survival in different peripheral tissues. 134,135 This association between NO-cGMP signaling and tau phosphorylation via pGSK3β activity is supported by the existence of a signaling cascade that links cGMP activation with GSK3 inhibition.…”